Might proton pump or sodium-hydrogen exchanger inhibitors be of value to ameliorate SARs-CoV-2 pathophysiology?
Physiol Rep
; 8(24): e14649, 2021 01.
Article
in English
| MEDLINE | ID: covidwho-1000668
ABSTRACT
Discovering therapeutics for COVID-19 is a priority. Besides high-throughput screening of compounds, candidates might be identified based on their known mechanisms of action and current understanding of the SARs-CoV-2 life cycle. Using this approach, proton pump (PPIs) and sodium-hydrogen exchanger inhibitors (NHEIs) emerged, because of their potential to inhibit the release of extracellular vesicles (EVs; exosomes and/or microvesicles) that could promote disease progression, and to directly disrupt SARs-CoV-2 pathogenesis. If EVs exacerbate SARs-CoV-2 infection as suggested for other viruses, then inhibiting EV release by PPIs/NHEIs should be beneficial. Mechanisms underlying inhibition of EV release by these drugs remain uncertain, but may involve perturbing endosomal pH especially of multivesicular bodies where intraluminal vesicles (nascent exosomes) are formed. Additionally, PPIs might inhibit the endosomal sorting complex for transport machinery involved in EV biogenesis. Through perturbing endocytic vesicle pH, PPIs/NHEIs could also impede cleavage of SARs-CoV-2 spike protein by cathepsins necessary for viral fusion with the endosomal membrane. Although pulmonary epithelial cells may rely mainly on plasma membrane serine protease TMPRSS2 for cell entry, PPIs/NHEIs might be efficacious in ACE2-expressing cells where viral endocytosis is the major or a contributing entry pathway. These pharmaceutics might also perturb pH in the endoplasmic reticulum-Golgi intermediate and Golgi compartments, thereby potentially disrupting viral assembly and glycosylation of spike protein/ACE2, respectively. A caveat, however, is that facilitation not inhibition of avian infectious bronchitis CoV pathogenesis was reported in one study after increasing Golgi pH. Envelope protein-derived viroporins contributed to pulmonary edema formation in mice infected with SARs-CoV. If similar pathogenesis occurs with SARs-CoV-2, then blocking these channels with NHEIs could ameliorate disease pathogenesis. To ascertain their potential efficacy, PPIs/NHEIs need evaluation in cell and animal models at various phases of SARs-CoV-2 infection. If they prove to be therapeutic, the greatest benefit might be realized with the administration before the onset of severe cytokine release syndrome.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Proton Pumps
/
Sodium-Hydrogen Exchangers
/
Virus Internalization
/
Proton Pump Inhibitors
/
COVID-19 Drug Treatment
Type of study:
Experimental Studies
Limits:
Animals
/
Humans
Language:
English
Journal:
Physiol Rep
Year:
2021
Document Type:
Article
Affiliation country:
Phy2.14649
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